Alpha-1-adrenergic receptor agonist activity of clinical alpha-adrenergic receptor agonists interferes with alpha-2-mediated analgesia
| Autor: | Sandhya Rao, Elaine Tang, Cynthia V. Cheevers, Karen M. Kedzie, John E. Donello, Daniel W. Gil, Cynthia A. Manlapaz |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
N-Methylaspartate medicine.drug_class Analgesic Receptor agonist activity Pharmacology Clonidine Dinoprostone Mice Brimonidine Tartrate Receptors Adrenergic alpha-2 Quinoxalines medicine Excitatory Amino Acid Agonists Animals Drug Interactions Adrenergic alpha-Antagonists Injections Spinal Pain Measurement Mice Knockout Analgesics business.industry Brimonidine Prazosin Mice Inbred C57BL Anesthesiology and Pain Medicine Allodynia Hyperalgesia Tizanidine Exploratory Behavior Calcium Adrenergic alpha-1 Receptor Agonists medicine.symptom business Adrenergic alpha-Agonists medicine.drug |
| Zdroj: | Anesthesiology. 110(2) |
| ISSN: | 1528-1175 |
| Popis: | Background The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects. Methods Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays. Results Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold. Conclusions Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain. |
| Databáze: | OpenAIRE |
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